Abstract: Hypoxia is a key component of the tumour microenvironment, and it is linked to cell proliferation, angiogenesis, metabolism, and the tumour immune response. All of these variables may accelerate tumour growth, increase tumour aggressiveness, raise tumour metastatic potential, and result in a poor prognosis. The goal of this trial was to determine if the pharmaceutical substance Ometaxine mepesuccinate, commonly known as Homoharringtonine or (HHT), is effective. Cephalotaxus fortunei is the source of natural plant alkaloids. HHT is a chemical derived from traditional Chinese medicine that has been licenced by the Food and Drug Administration for the treatment of leukaemia. Previous research has suggested that HHT might limit protein synthesis and promote apoptosis by upregulating the proapoptotic protein Bax and triggering the caspase-3-mediated cleavage of PARP. Aside from hematologic tumours, HHT has also been shown to be useful in renal cell carcinoma, colon rectal cancer, and non-small cell lung cancer. The impact of HHT on CRC, as well as the underlying HIF-1/VEGF-associated mechanisms of action, have not been explored. Tube formation was used to measure in vitro angiogenesis. A cell viability assay, scratch assay, real-time PCR, enzyme-linked immunosorbent assay and immunoblotting were used to analyse the gene and protein expressions of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF). The development of hypoxic HUVEC cell tubes is inhibited by HHT. In CRC SW480 cells, HHT reduced hypoxia-induced VEGF overexpression at both the mRNA and protein levels. Furthermore, HHT suppressed HIF-1a-induced angiogenesis in vitro via inhibiting HIF-induced ERK phosphorylation. Hypoxia raised HIF-1 mRNA and protein levels, which were all suppressed by HHT. Hypoxia significantly elevated ERK and AKT phosphorylation in CRC cells, which HHT reduced. By reducing HIF-1/VEGF-mediated intercellular communication between CRC cells and endothelial cells, HHT decreased hypoxic CRC cell-induced angiogenesis. We think that HHT could be an ideal candidate for CRC tumour inhibition and needs more investigation for further study.